ABSTRACT Osteoarthritis (OA) is one of the most common forms of arthritis and characterized by progressive degradation of cartilage. There is no cure for OA and is a largely unmet medical need for disease-modifying and symptomatic treatment. Systemic delivery of morphogens and growth factors supporting cartilage matrix synthesis, such as insulin like growth factor-1 (IGF-1) and/or transforming growth factor- ? (TGF-?3), often results in poor improvement due to the lack of vascularity within intra-articular spaces. Therefore, localized intra-articular administration of growth factors targeting cartilage regeneration has emerged as a promising strategy for therapeutic intervention in OA. The objective of this R03 proposal is to develop nanosilicates for sustained delivery of OA-modifying therapeutics (IGF-1/ TGF-?3) to promote chondrocyte proliferation and maturation. Our central hypothesis is that sustain release of OA-modifying therapeutics will promote cartilaginous ECM production. The specific aims of this work are: (1) Understand the biological response of nanosilicates with human cells, and (2) Investigate the efficacy of therapeutic loaded nanosilicates to induce chondrogenic differentiation and production of cartilaginous ECM. The proposed research has tremendous transformative potential in the areas of therapeutic delivery, cartilage regeneration, stem cell research and OA treatment. Specifically, this project will introduce nanosilicates as a ?plug-and-play? type of therapeutics delivery platform for various tissue-engineering applications. In addition, the project will also result in a fundamental shift in our understanding of mineral-induced cellular behavior, opening up an entirely new avenue in regenerative medicine. Upon completion, we believe that our results will have a significant, positive impact on regeneration of injured cartilage in patients suffering from osteoarthritis, for whom current treatment options remain limited. !